The four members of the epidermal growth factor receptor (ErbB) family of hormone receptors are forefront targets for the new generation of FDA-approved rational cancer therapeutics, including Herceptin, Cetuximab, Tykerb, and Tarceva. The first receptor (EGF receptor) is a therapeutic target in two of the greatest human cancer killers: non-small cell lung carcinoma and colon carcinoma. The second receptor, HER2/neu/ErbB2, is a validated therapeutic target in breast cancer. In contrast, the role of the fourth receptor, ErbB4, is uncertain. There are four different forms of this receptor with different structures. Preliminary evidence indicates that each form of ErbB4 has unique functions, with some forms having opposite effects on processes related to cancer. We will determine what the functions of these four ErbB4 receptor forms are, and how this relates to the well-being of cancer patients expressing these forms. The results will have important implications for human cancer treatment, including whether ErbB4 is a reasonable therapeutic target, and may identify unique biological functions for ErbB4 that may be harnessed in cancer therapies. The work will reveal whether there are subsets of patients with strong ErbB4 activity that potentially would be harmed by EGFR and ErbB2-directed therapies. This work will also be important in other human diseases involving ErbB4. Neuregulin-1, one of the hormones that activates ErbB4, may have therapeutic potential in cardiovascular disease, and has been linked to schizophrenia and bipolar disorder. Presenilin-dependent cleavage of ErbB4, may be important in Alzheimer's Disease. Aim 1 will create mouse models for determining the differential effects of the ErbB4 forms on mammary development. This will reveal which of these forms affects which normal processes. Aim 2 will first use the mouse models from Aim 1 to evaluate positive and negative effects on development of breast cancer. Then, we will determine the clinical correlations of excessive expression of these individual ErbB4 isoforms in a set of nearly 1000 human breast cancers with sixteen years patient follow up information. This will directly test the impact of individual isoforms on patient prognosis. Aim 3 will evaluate unique features of cell regulation by ErbB4 forms that act in the cell nucleus. This affords ErbB4 the ability to reprogram major cell activities, some relevant to cancer. These experiments will provide a global view of these functions.